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warnings
WARNINGS Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias) Conditions That Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. If the infusion rate is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature) Children <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor pulmonale Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants <3 months of age Sepsis with multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin) (see PRECAUTIONS , Drug Interactions , Table II ). When Signs or Symptoms of Theophylline Toxicity Are Present: Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately. Dosage Increases Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is <10 mcg/mL. As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION , TABLE VI ).
ADVERSE REACTIONS Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Products containing aminophylline may rarely produce severe allergic reactions of the skin, including exfoliative dermatitis, after systemic administration in a patient who has been previously sensitized by topical application of a substance containing ethylenediamine. In such patients skin patch tests are positive for ethylenediamine, a component of aminophylline, and negative for theophylline. Pharmacists and other individuals who experience repeated skin exposure while physically handling aminophylline may develop a contact dermatitis due to the ethylenediamine component. Table IV. Manifestations of Theophylline Toxicity* Percentage of Patients Reported With Sign or Symptom * These data are derived from two studies in patients with serum theophylline concentrations >30 mcg/mL. In the first study (Study #1 – Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 – Sessler, Am J Med 1990; 88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. ** NR = Not reported in a comparable manner. Acute Overdose (Large Single Ingestion) Chronic Overdosage (Multiple Excessive Doses) Sign/Symptom Study 1 (n=157) Study 2 (n=14) Study 1 (n=92) Study 2 (n=102) Asymptomatic NR** 0 NR** 6 Gastrointestinal Vomiting 73 93 30 61 Abdominal pain NR** 21 NR** 12 Diarrhea NR** 0 NR** 14 Hematemesis NR** 0 NR** 2 Metabolic/Other Hypokalemia 85 79 44 43 Hyperglycemia 98 NR** 18 NR** Acid/base disturbance 34 21 9 5 Rhabdomyolysis NR** 7 NR** 0 Cardiovascular Sinus tachycardia 100 86 100 62 Other supraventricular 2 21 12 14 tachycardias Ventricular premature beats 3 21 10 19 Atrial fibrillation or flutter 1 NR** 12 NR** Multifocal atrial tachycardia 0 NR** 2 NR** Ventricular arrhythmias with 7 14 40 0 hemodynamic instability Hypotension/shock NR** 21 NR** 8 Neurologic Nervousness NR** 64 NR** 21 Tremors 38 29 16 14 Disorientation NR** 7 NR** 11 Seizures 5 14 14 5 Death 3 21 10 4
adverse reactions table
<table ID="_Ref418696861" width="100%"><caption>Table IV. Manifestations of Theophylline Toxicity* Percentage of Patients Reported With Sign or Symptom</caption><col width="34%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="16%"/><tfoot><tr><td align="left" colspan="5" valign="top">* These data are derived from two studies in patients with serum theophylline concentrations >30 mcg/mL. In the first study (Study #1 – Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 – Sessler, Am J Med 1990; 88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. ** NR = Not reported in a comparable manner. </td></tr></tfoot><tbody><tr><td styleCode="Toprule " valign="top"/><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Acute Overdose</content></paragraph><paragraph><content styleCode="bold">(Large Single Ingestion)</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Chronic Overdosage</content></paragraph><paragraph><content styleCode="bold">(Multiple Excessive Doses)</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="bottom"><paragraph><content styleCode="bold">Sign/Symptom</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Study 1</content></paragraph><paragraph><content styleCode="bold">(n=157)</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Study 2</content></paragraph><paragraph><content styleCode="bold">(n=14)</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Study 1</content></paragraph><paragraph><content styleCode="bold">(n=92)</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Study 2</content></paragraph><paragraph><content styleCode="bold">(n=102)</content></paragraph></td></tr><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="underline">Asymptomatic</content></paragraph></td><td align="center" styleCode="Toprule " valign="middle"><paragraph> NR**</paragraph></td><td align="center" styleCode="Toprule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Toprule " valign="middle"><paragraph> NR**</paragraph></td><td align="center" styleCode="Toprule " valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="underline">Gastrointestinal</content></paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="top"><paragraph> Vomiting</paragraph></td><td align="center" valign="middle"><paragraph> 73</paragraph></td><td align="center" valign="middle"><paragraph> 93</paragraph></td><td align="center" valign="middle"><paragraph> 30</paragraph></td><td align="center" valign="middle"><paragraph> 61</paragraph></td></tr><tr><td valign="top"><paragraph> Abdominal pain</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 21</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 14</paragraph></td></tr><tr><td valign="top"><paragraph> Hematemesis</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="underline">Metabolic/Other</content></paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" valign="middle"><paragraph> 85</paragraph></td><td align="center" valign="middle"><paragraph> 79</paragraph></td><td align="center" valign="middle"><paragraph> 44</paragraph></td><td align="center" valign="middle"><paragraph> 43</paragraph></td></tr><tr><td valign="top"><paragraph> Hyperglycemia</paragraph></td><td align="center" valign="middle"><paragraph> 98</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 18</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td></tr><tr><td valign="top"><paragraph> Acid/base disturbance</paragraph></td><td align="center" valign="middle"><paragraph> 34</paragraph></td><td align="center" valign="middle"><paragraph> 21</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="top"><paragraph> Rhabdomyolysis</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="underline">Cardiovascular</content></paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="top"><paragraph> Sinus tachycardia</paragraph></td><td align="center" valign="middle"><paragraph> 100</paragraph></td><td align="center" valign="middle"><paragraph> 86</paragraph></td><td align="center" valign="middle"><paragraph> 100</paragraph></td><td align="center" valign="middle"><paragraph> 62</paragraph></td></tr><tr><td valign="top"><paragraph> Other supraventricular</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph> 21</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td align="center" valign="middle"><paragraph> 14</paragraph></td></tr><tr><td valign="top"><paragraph> tachycardias</paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="top"><paragraph> Ventricular premature beats</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph> 21</paragraph></td><td align="center" valign="middle"><paragraph> 10</paragraph></td><td align="center" valign="middle"><paragraph> 19</paragraph></td></tr><tr><td valign="top"><paragraph> Atrial fibrillation or flutter</paragraph></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 12</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td></tr><tr><td valign="top"><paragraph> Multifocal atrial tachycardia</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td></tr><tr><td valign="top"><paragraph> Ventricular arrhythmias with</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph> 14</paragraph></td><td align="center" valign="middle"><paragraph> 40</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph> hemodynamic instability</paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="top"><paragraph> Hypotension/shock</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 21</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="underline">Neurologic</content></paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="top"><paragraph> Nervousness</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 64</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 21</paragraph></td></tr><tr><td valign="top"><paragraph> Tremors</paragraph></td><td align="center" valign="middle"><paragraph> 38</paragraph></td><td align="center" valign="middle"><paragraph> 29</paragraph></td><td align="center" valign="middle"><paragraph> 16</paragraph></td><td align="center" valign="middle"><paragraph> 14</paragraph></td></tr><tr><td valign="top"><paragraph> Disorientation</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph> NR**</paragraph></td><td align="center" valign="middle"><paragraph> 11</paragraph></td></tr><tr><td valign="top"><paragraph> Seizures</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph> 14</paragraph></td><td align="center" valign="middle"><paragraph> 14</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="underline">Death</content></paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph> 21</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph> 10</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td></tr></tbody></table>